The research objectives of all three projects requires isogenic and xenogeneic animal models of cancer initiation, progression, invasion, and metastasis for their studies. The Animals Models Core was established as a central facility for all three Projects and the two scientific Cores to develop novel mouse models for the program investigators and to provide transgenic and gene-specific homozygous null mice on defined backgrounds for the testing of potential drugs and gene modulation therapies. The Animal Models Core will continue to make models and breed mice onto specific backgrounds, provide sufficient mice of defined genotype for the research needs of the Projects. It will also coordinate injections and clinical examinations for the preclinical evaluations of novel protease inhibitors. The new animal models and the defined quality of the animals make this a cost-effective resource for the entire program. The Core will generate and/or breed MT-SP1, metalloproteinases (MMPs), or protease inhibitor nullmutant mice and MT-SP1 and protease inhibitor transgenic mice onto backgrounds suitable for the animals model studies to test them in cancer development, progression, and therapy models and provide the mice to individual Projects. Planned are: MT-SP1, MMP8, MMP13, cathepsin B, and dipeptidyl peptidase I (DPP1) single nulls, and MMP2/MMP9, MMP3/MMP9, and MMP2/MMP3 double nulls, all bred onto either FVB/n or C57BL6 backgrounds, as appropriate. It will develop mouse lines transgenic for protease inhibitors, as required, driven by regulated promoters, and breed these onto defined backgrounds for the laboratory programs. It will generate MMP null and MT-SP1 null mice on the RAG1 null background for experiments with transplantation of allogeneic and xenogeneic (human) tumors. Planned are RAG1/MMP2 double null, RAG1/MT-SP1 double null, and RAG1/MMP2/MMP9 triple nulls. It will test specific protease inhibitors for short-term in vivo efficacy using protease-dependent biological events and test specific protease inhibitors for long-term preclinical trials for in vivo efficacy in protease-dependent events. The Animals Models Core is a resource that will support all three programs of the grant and provide tissue and mice for the other scientific Cores. It will remain flexible to support the needs of the investigators.